Biomedicines (Oct 2024)

PEP-1–PIN1 Promotes Hippocampal Neuronal Cell Survival by Inhibiting Cellular ROS and MAPK Phosphorylation

  • Jung Hwan Park,
  • Min Jea Shin,
  • Gi Soo Youn,
  • Hyeon Ji Yeo,
  • Eun Ji Yeo,
  • Hyun Jung Kwon,
  • Lee Re Lee,
  • Na Yeon Kim,
  • Su Yeon Kwon,
  • Su Min Kim,
  • Yong-Jun Cho,
  • Sung Ho Lee,
  • Hyo Young Jung,
  • Dae Won Kim,
  • Won Sik Eum,
  • Soo Young Choi

DOI
https://doi.org/10.3390/biomedicines12102352
Journal volume & issue
Vol. 12, no. 10
p. 2352

Abstract

Read online

Background: The peptidyl-prolyl isomerase (PIN1) plays a vital role in cellular processes, including intracellular signaling and apoptosis. While oxidative stress is considered one of the primary mechanisms of pathogenesis in brain ischemic injury, the precise function of PIN1 in this disease remains to be elucidated. Objective: We constructed a cell-permeable PEP-1–PIN1 fusion protein and investigated PIN1’s function in HT-22 hippocampal cells as well as in a brain ischemic injury gerbil model. Methods: Transduction of PEP-1–PIN1 into HT-22 cells and signaling pathways were determined by Western blot analysis. Intracellular reactive oxygen species (ROS) production and DNA damage was confirmed by DCF-DA and TUNEL staining. Cell viability was determined by MTT assay. Protective effects of PEP-1-PIN1 against ischemic injury were examined using immunohistochemistry. Results: PEP-1–PIN1, when transduced into HT-22 hippocampal cells, inhibited cell death in H2O2-treated cells and markedly reduced DNA fragmentation and ROS production. This fusion protein also reduced phosphorylation of mitogen-activated protein kinase (MAPK) and modulated expression levels of apoptosis-signaling proteins in HT-22 cells. Furthermore, PEP-1–PIN1 was distributed in gerbil hippocampus neuronal cells after passing through the blood–brain barrier (BBB) and significantly protected against neuronal cell death and also decreased activation of microglia and astrocytes in an ischemic injury gerbil model. Conclusions: These results indicate that PEP-1–PIN1 can inhibit ischemic brain injury by reducing cellular ROS levels and regulating MAPK and apoptosis-signaling pathways, suggesting that PIN1 plays a protective role in H2O2-treated HT-22 cells and ischemic injury gerbil model.

Keywords